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CANCER GENOMICS & PROTEOMICS 10 : 169-186 (2013)

Review

The Role of in Cancer: Possible Genetic and Cellular Signaling Mechanisms KHANH VINH QUỐC LƯƠNG and LAN THI HOÀNG NGUYỄN

Vietnamese American Medical Research Foundation, Westminster, CA, U.S.A.

Abstract. The relationship between supplemental may exhibit some antitumor effects. The role of thiamine in and various types of cancer has been the focus of recent cancer is controversial. However, may investigation, and supplemental vitamins have been reported occur in patients with cancer and cause serious disorders, to modulate cancer rates. A significant association has been including Wernicke’s encephalopathy, that require parenteral demonstrated between cancer and low levels of thiamine in the thiamine supplementation. A very high dose of thiamine serum. Genetic studies have helped identify a number of produces a growth-inhibitory effect in cancer. Therefore, factors that link thiamine to cancer, including the solute further investigations of thiamine in cancer are needed to carrier transporter (SLC19) gene, transketolase, transcription clarify this relationship. factor p53, poly(ADP-ribose) polymerase-1 gene, and the reduced form of adenine dinucleotide phosphate. The relationship of supplemental vitamins and various types Thiamine supplementation may contribute to a high rate of of cancer has been the focus of recent investigations, and tumor cell survival, proliferation and chemotherapy resistance. supplemental vitamins have been reported to modulate Thiamine has also been implicated in cancer through its cancer rates. In a New Hampshire study, higher total intakes effects on matrix metalloproteinases, prostaglandins, of carotenoids, D, thiamine, , and cyclooxygenase-2, reactive oxygen species, and nitric oxide were inversely related to bladder cancer risk among older synthase. However, some studies have suggested that thiamine individuals (1). Higher intake of , beta-carotene, thiamine, and nicotinic acid was also associated with a decrease in gastric cancer risk in a case control study (2). In Hawaii, and thiamine levels from food sources Abbreviations: 15-PGDH: 15- Hydroxyprostaglandin dehydrogenase; exhibited an inverse relationship with incidence of high- ATTP: adenosine thiamine triphosphate; CNS: central nervous system; DKA: diabetic ketoacidosis; ECM: extracellular matrix; COX: grade squamous intraepithelial lesions of the cervix (3). In cyclooxygenase; DM: diabetes mellitus; HCC: hepatocellular Poland, higher consumption of alcohol, when combined carcinoma; KTS: 3-ethoxy-2-oxobutyraldehyde bis(thiosemi- with a low intake of , thiamine or antioxidant carbazone); iNOS: inducible NOS; MMP: matrix metalloproteinase; micronutrients, increased the risk of colorectal cancer and NADPH: the reduced form of nicotinamide adenine dinucleotide established a cancer-preventive role for retinol and thiamine phosphate; NO: nitric oxide; NOS: nitric oxide synthase; NOX: the (4). High dietary intake of vitamin C and thiamine has been NADPH oxidase; LPS: lipopolysaccharide; PARP-1: Poly(ADP-ribose) reported to reduce the risk of prostate cancer in China (5). polymerase-1; PDH: pyruvate dehydrogenase; PG: prostaglandins; et al. RDA: recommended dietary allowance; ROS: reactive oxygen species; In another study, Hargreaves (6) suggested that low SLC: solute carrier transporter; SOD: superoxide dismutase; TD: intake of thiamine, riboflavin, vitamins A and C, and iron thiamine-deficient; TDP: thiamine diphosphate; ThTk: thiamine may contribute to cancer risk in African-Americans. When transporter; TKTL-1: transketolase-like 1; TPP: ; monitoring micronutrient levels in gastrointestinal cancer, TIMP-1: tissue inhibitor of metalloproteinase-1. plasma vitamin C and red blood cell thiamine levels were significantly reduced in weight-losing patients with cancer Correspondence to: Khanh v.q. Lương, MD, FACP, FACE, FACN, compared with their weight-stable counterparts, and weight- FASN, FCCP, and FACAAI (SC), 14971 Brookhurst St. Westminster, CA 92683, U.S.A. Tel: +1 7148395898, Fax: +1 losing patients exhibited lower vitamin C and thiamine 7148395989, email: [email protected] intake (7). Furthermore, patients with acute leukemia exhibit ed low thiamine content in leukocytes and blood Key Words: Thiamine, cancer, vitamin B1, transketolase, tumor, plasma (8). The thiamine pyrophosphate (TPP) stimulating review. effect and urinary excretion of thiamine were high in

1109 -6535 /2013 169 CANCER GENOMICS & PROTEOMICS 10 : 169-186 (2013) patients with breast and bronchial carcinomas, suggesting Transketolase. Thiamine acts as a co- for that these patients may be at risk for thiamine deficiency transketolase, pyruvate dehydrogenase (PDH), and α- (9). Transketolase reactions play a crucial role in the use of ketoglutarate dehydrogenase complexes, which contain glucose carbons in tumo r cell synthesis of nucleic acid with fundamental roles in intracellular glucose ribose. Experimentally, a dramatic decrease in tumor cell . Thiamine also regulates the expression of genes proliferation was observed in several in vitro and in vivo that code for enzymes using thiamine as a co-factor. Thiamine tumor models after administering the transketolase inhibitor deficiency reduces the mRNA levels of transketolase and oxythiamine (10, 11). Supplementation with excess thiamine PDH (34). In the blood of patients with cancer, the and in tumor-bearing rats reduced growth concentration of thiamine and thiamine diphosphate (TDP) restriction and enhanced the antitumor activity of 3-ethoxy- are lowered by 20%; transketolase activity is decreased by 2-oxobutyraldehyde bis(thiosemicarbazone) (KTS). 20%, and the TDP effect by 5-42% (35). Moreover, aberrant Similarly, the addition of thiamine protected the KTS- levels of transketolase and transketolase-like-1 (TKTL-1) treated rats from weight loss in a dose-related manner (12). participated in glucose metabolism in malignant cells in These findings suggest that thiamine may be associated with pleural effusion (36). TKTL-1 has been reported to play a cancer. Therefore, we reviewed th e role of thiamine in pivotal role in carcinogenesis and has an important role in cancer. controlling the non-oxidative pentose-phosphate pathway, which is significantly up-regulated in cancer. Increased The Genomic Factors Associated with TKTL-1 expression has been shown to be correlated with Thiamine in Cancer poor patient outcome and increased tumor progression (37). Additionally, increased TKTL 1 has been observed in many The solute carrier (SLC) transport protein. The SLC19 types of cancer, including thyroid cancer (38, 39), gene is a family of three transporter proteins with nasopharyngeal carcinoma (40, 41), non-small cell lung significant structural similarit ies , but each protein binds cancer (42, 43), gastric cancer (44), human hepatoma cell substrates with different structures and ionic charges. The (45), colorectal cancer (46), urothelial cancer (47), anaplastic SLC19 gene family plays an important role in the transport nephroblastoma (48), breast cancer (49), endometrial cancer and homeostasis of and thiamine in the body (13). (50), ovarian cancer (51, 52), cancer of the uterine cervix SLC19A2 and SLC19A3 mediate the transport of thiamine (53), head and neck cancer (54), and glioblastoma (55). (14, 15). SLC19A3 RNA levels have been reported to be However, the related proteins TKTL-1 and TKTL-2 lack down-regulated in breast and lung cancer compared with numerous invariant residues involved in co-factor and adjacent normal tissues (16, 17). The SLC19A3 gene is substrate binding of TPP and are therefore not expected to regulated by exogenous thiamine in a manner similar to the possess transketolase activity (56). effect of SLC19A3 overexpression (17). SLC19A3 expression is down-regulated in gastric cancer cell lines Transcription factor p53. The p53 gene and protein play a (71%) and restored after pharmaceutical demethylation. critical role in the regulation of the normal cell cycle, cell Ex og enous SLC19A3 expression causes growth inhibition cycle arrest, and the apoptotic response. p53 is a transcription of gastric cancer cells (17). SLC19A3 gene expression is factor with a major role in determining cell fate in response to down-regulated in breast cancer and associated with DNA damage. p53 reduces the incidence of cancer by resistance to apoptosis in these tumors (18). Its mRNA promoting apoptosis in cells that have activated oncogenic expression is also down-regulated by DNA methylation, pathways. p53 polymorphisms have been demonstrated in and by histone deacetylation in colon cancer cells (19). breast cancer (57), mesothelioma (58), esophageal squamous However, hypoxia induces the up-regulation and function cell carcinoma (59), and pancreatic cancer (60). In many of the SLC19A3 gene in a breast cancer cell line (20). meta-analyses, p53 polymorphisms have been reported to be Aberrant SLC19A3 has been suggested as a novel associated with cervical (61), gastric (62), bladder (63), biomarker for breast and gastric cancer diagnosis (21). colorectal (64), and endometrial (65) cancer, but not with SLC19A2 has also been shown to transport mono- and prostate cancer (66). Increased thiamine transporter levels pyrophosphate derivatives of thiamine (22, 23). have been observed in murine cells that overexpress mouse Polymorphisms of SLC19A1 are reported in many types of SLC19A2 or in cells exposed to conditions that induce DNA cancers, such as osteosarcoma (24), colorectal cancer (25), damage or p53 activation (67). TDP has been shown to inhibit non-small cell lung cancer (26), bladder cancer (27), p53 binding and thiamine has been shown to inhibit prostate cancer (28), diffuse large B-cell lymphoma (29), intracellular p53 activity (68). The expression of p53 pediatric acute lymphoblastic leukemia (30), head and neck decreased significantly in cultured retinal neurons of diabetic cancer (31), central nervous system (CNS) tumors in Thai rats treated with thiamine (69). These observations suggested children (32), and human ovarian carcinoma cells (33). that the transcription factor p53 is activated in cancer with

170 Lương et al : Thiamine and Cancer (Review) increasing apoptotic response from cellular damage and (95), esophageal adenocarcinoma (96), HCC (97), prostate thiamine ameliorated these effects on cells. cancer (98), colon cancer (99), glioblastoma multiforme (100), and multiple myeloma (101). NADPH polymorphisms Poly(ADP-ribose) polymerase-1 (PARP-1). PARP 1 is a have been reported to be associated with myelodysplastic nuclear protein that contributes to both cell death and syndrome and de novo acute myeloid leukemia (102, 103), survival under stressful conditions. PARP-1 catalytic activity esophagus cancer (104), lung cancer (105, 106), non- is stimulated by DNA strand breaks. In mice, Parp-1 - Hodgkin’ s lymphoma (107, 108), childhood acute leukemia deficient cells exhibited enhanced sensitivity to lethal effects (109), postmenopausal breast cancer (110), and gastric of ionizing radiation and alkylating agents (70), and Parp-1 cancer (111). The levels of NADPH cytochrome c reductase knockout mice were found to develop spontaneous mammary are increased in thiamine-deficient animals (112). The and liver tumors (71, 72). Overexpression of PARP-1 has expression of NOX4 is significantly down-regulated by been reported in Ewing’s sarcoma (73), malignant lymphoma benfotiamine treatment under both normo- and (74), colorectal cancer (75), hepatocellular carcinoma (HCC) hyperglycemic conditions (113). In addition, animals fed a (76), breast cancer (77), pediatric CNS tumors (78), and high thiamine diet exhibited NADPH-cytochrome c reductase ovarian cancer (79). In a meta-analysis, PARP-1 mRNA activity of approximately 57% that of those fed a thiamine- expression was correlated with high-grade, medullary deficient (TD) diet (114). Altogether, these results suggest histological type, tumor size, and worse metastasis-free that thiamine may produce a cancer-protective effect by survival and overall survival in human breast cancer (80). regulating NADPH-cytochrome c activity. PARP-1 polymorphisms have been found to be associated The genetic factors related to thiamine and cancer are with gastric cancer in Han Chinese (81), prostate cancer (82), summarized in Table I. esophageal squamous cell carcinoma (83), and lung cancer (84), and with a reduced risk of non-Hodgkin lymphoma in The Role of Thiamine in Cancer Korean males (85). PARP 1 polymorphisms reduce PARP-1 catalytic activity by 30-40% (86). In a meta-analysis, no Diabetes mellitus. Alterations in glucose metabolism have significant association was observed between the PARP-1 been linked to a significantly increased risk for many forms V762 polymorphism and cancer risk; however, the variant A of cancer. Gestational diabetes mellitus (DM), a state of allele of the PARP-1 V762 polymorphism was associated glucose intolerance associated with pregnancy, is associated with an increased risk of cancer within Asian populations, with an increased risk of pancreatic cancer and but with a decreased risk of cancer among Caucasians, hematologic al malignancies (115). DM and impaired particularly for glioma (87). However, thiamine has a glucose metabolism contribute to the risk of postmenopausal cytoprotective effect on cultured neonatal rat cardiomyocytes breast and endometrial cancer (116). The metabolic under hypoxic insult; thiamine also inhibits PARP cleavage syndrome has been reported to be associated with the risk and DNA fragmentation (88). Benfotiamine, a fat-soluble of prostate cancer in Italian populations (117). Type 1 DM is thiamine analog, prevents bacterial endotoxin-induced associated with an increase in the risk of cancer, particularly inflammation and PARP cleavage in mouse macrophage cell gastric, uterine cervix, endometrial, and ovarian cancer (118, lines (89). Adenosine thiamine triphosphate (ATTP) has been 119). Several meta-analyses have demonstrated an identified in small amounts in the mouse brain, heart, association between DM and increased cancer risk, skeletal muscle, liver and kidneys (90) and has been shown including esophageal (120), gastric (121), colorectal (122), to inhibit PARP-1 activity (91). Taken together, the results HCC (123), cholangiocarcinoma (124), and breast cancer indicate that thiamine may play a role in cancer by (125). The incidence of DM in renal cell carcinoma is modulating PARP-1 activity. higher in females than males and higher in Hispanic populations compared to Caucasian populations and other The reduced form of nicotinamide adenine dinucleotide ethnicities (126). However, a relationship between thiamine phosphate (NADPH). The NADPH oxidase (NOX) enzyme and DM has also been reported in the literature. A complex mediates critical physiological and pathological significant proportion of healthy individuals (36-47%) have processes, including cell signaling, inflammation and been reported to have thiamine deficiency while in a mitogenesis, through the generation of reactive oxygen hyperglycemic state (such as on a diet high in carbohydrates species (ROS) from molecular oxygen. NOX1 is required for or if diabetic or pregnant) (127). Low plasma thiamine RAS oncogene-induced cell transformation (92). The NOX levels have been noted in patients with DM type 1 (128). subunit p22 phox has been reported to inhibit the function of Thiamine reserves are reduced in litters of untreated diabetic the tumor suppressor protein tuberin in renal carcinoma cells rats (129). In children, acute thiamine deficiency can be (93). The activation of NOXs has been demonstrated in the manifested as diabetic ketoacidosis (DKA), lactic acidosis development of cancer, including melanoma (94), leukemia and hyperglycemia (130, 131). In another study, low blood

171 CANCER GENOMICS & PROTEOMICS 10 : 169-186 (2013)

Table I. Genetic factors related to thiamine and cancer.

Cancer Thiamine

SLC19 gene A1 *SLC19A1 Polymorphisms have been reported in many *Plays an important role in the transport and cancers, including osteosarcoma, colorectal cancer, non-small homeostasis of folate and thiamine in the body. cell lung cancer, bladder cancer, prostate cancer, diffuse *Transports mono- and pyrophosphate large B-cell lymphoma, pediatric acute lymphoblastic derivative s of thiamine. leukemia, head and neck cancer, central nervous system tumors in Thai children, and human ovarian carcinoma cells. A2 (ThTr1) *SLC19A3 RNA levels are down-regulated in breast *Mediates the transport of thiamine. and lung cancers compared with adjacent normal tissues. A3 (ThTr2) *SLC19A3 expression is down-regulated in gastric cancer *Mediates the transport of thiamine. cell lines (71%) and restored after pharmaceutical demethylation. Exgonenous SLC19A3 expression caused *SLC19A3 gene also exhibited evidence of regulation growth inhibition of gastric cancer cells. by exogenous thiamine in a manner concordant *SLC19A3 gene expression is down-regulated in breast cancer with the effects of SLC19A3 overexpression. and associated with resistance to apoptosis in the se tumors. *Aberrant SLC19A3 has been suggested as a novel biomarker for breast and gastric cancer diagnosis.

Transketolase *Aberrant TK and TK-like 1 (TKTL-1) expression has been *Thiamine regulates the expression of genes that (TK) reported to participate in glucose metabolism in malignant code for enzymes that use thiamine as co-factor. pleural effusion cells. TKTL-1 has been reported to play Thiamine deficiency diminishes the mRNA levels a pivotal role in carcinogenesis and has an important role in of TK. In the blood of cancer patients, controlling the non-oxidative pentose-phosphate-pathway, the concentration of thiamine and thiamine diphosphate which is significant in cancer. TKTL-1 expression has been (TDP) are decreased by 20%; Tk activity is decreased correlated with poor patient outcome and tumor progression. by 20% and the TDP effect is altered by 5-42%. *Overexpression of TKTL-1 has been observed in many cancers, including thyroid cancer, nasopharyngeal carcinoma, non-small cell lung cancer, gastric cancer, human hepatoma cell, colorectal cancer, urothelial cancer, anaplastic nephroblastoma, breast cancer, endometrial cancer, ovarian cancer, uterine cervix cancer, head and neck cancer, and glioblastoma. p53 gene *Plays a critical role in the regulation of the normal cell *Increased thiamine transporter activity has been cycle, cell cycle arrest, and apoptotic response. reported in cells that overexpress the genes that code *Transcription factor that has a major role in determining for thiamine transporters and under conditions cell fates in response to DNA damage. of DNA damage or p53 activation. *The function of p53 is to mediate apoptosis in cells *TDP has been shown to inhibit p53 binding and that have activated oncogenic pathways. thiamine has been shown to inhibit *p53 polymorphisms have been demonstrated intracellular p53 activity. in breast cancer, mesothelioma, esophageal *The expression of p53 was decreased significantly squamous cellcarcinoma, and pancreatic cancer. in cultured retinal neurons of diabetic *In many meta-analyses, p53 polymorphisms have been rats treated with thiamine. associated with cervical, gastric, bladder, colorectal, and endometrial cancer, but not with prostate cancer.

Poly(ADP-ribose) *PARP-1 is a nuclear protein that contributes to both *Thiamine has a cytoprotective effect on cultured polymerase-1 cell death and survival under stressful conditions. neonatal rat cardiomyocytes under hypoxic insult. (PARP 1) The catalytic activity of PARP-1 is stimulated Thiamine also inhibits PARP cleavage by DNA strand breaks. and DNA fragmentation. *Parp-1-deficient cells exhibit enhanced sensitivity *Benfotiamine, a fat-soluble thiamine analog, prevents to the lethal effects of ionizing radiation and bacterial endotoxin-induced inflammation and alkylating agents, and Parp-1 knockout mice PARP cleavage in mouse macrophage cell lines. developed spontaneous mammary and liver tumors. *Adenosine thiamine triphosphate, a thiamine *Overexpression of PARP-1 has been reported in Ewing’s derivative, has been identified in small amounts in sarcoma, malignant lymphomas, colorectal cancer, the mouse brain, heart, skeletal muscle, liver and hepatocellular carcinoma, breast cancer, pediatric kidneys and has been shown to inhibit PARP-1 activity. central nervous system tumors, and ovarian cancer.

Table I. Continued

172 Lương et al : Thiamine and Cancer (Review)

Table I. Continued

Cancer Thiamine

*In a meta-analysis, PARP-1 mRNA expression was correlated with high grade, medullary histological type, tumor size, and decreased metastasis-free survival and overall survival in human breast cancer. *PARP-1 polymorphism has been associated with gastric cancer in the Han Chinese, prostate cancer, esophageal squamous cell carcinoma, and lung cancer, but it also associated with a reduced risk of non-Hodgkin’ s lymphoma in Korean males. PARP 1 polymorphism reduces PARP-1 catalytic activity by 30-40%. *In a meta-analysis study, no significant association was observed between the PARP-1 V762 polymorphism and cancer risk; however, the variant A allele of the PARP-1 V762 polymorphism was associated with an increased risk of cancer among Asian populations but a decreased risk of cancer among Caucasians, particular for glioma.

The reduced form of *Mediates critical physiological and pathological processes the nicotinamide including cell signaling, inflammation and mitogenesis adenine dinucleotide through the generation of reactive oxygen species from phosphate (NADPH) molecular oxygen. oxidase (NOX) *NOX1 is required for RAS oncogene-induced *The levels of NADPH cytochrome c reductase enzyme complex cell transformation. are increased in thiamine-deficient (TD) animals. *The NOX subunit p22 phox has been reported *The expression of NOX4 is significantly to inhibit the function of t he tumor suppressor down-regulated by benfotiamine treatment under protein tuberin in renal carcinoma cells. both normo- and hyperglycemic conditions. *The activation of NOX has been demonstrated *Animals fed a high thiamine diet exhibited an in the development of several types of cancer, NADPH-cytochrome c reductase activity that was including melanoma, leukemia, esophageal, approximately 57% of those fed a TD diet. hepatocellular carcinoma, prostate, colon, glioblastoma multiforme, and multiple myeloma. *NADPH polymorphisms have been associated with myelodysplastic syndrome and de novo acute myeloid leukemia, esophageal cancer, lung cancer, non-Hodgkin’ s lymphoma, childhood acute leukemia, postmenopausal breast cancer, and gastric cancer.

thiamine levels in the blood and erythrocyte transketolase Cancer. Thiamine levels are decreased in many cancer activity, and high erythrocyte TPP activity were documented subjects. Hepatoma induced by butter-yellow exhibited a in patients with diabetes (132, 133). The activity of decrease in thiamine and co-enzyme A concentrations by transketolase has been used to assess thiamine activity in more than 50% and 92%, respectively, compared to normal mammalian tissues. The low thiamine values in patients liver s (135). Thiamine deficiencies have also been noted in with diabetes might be a reflection of reduced apo-enzyme patients with uterine cancer (136), B-chronic lymphocytic levels from the disease itself rather than from a thiamine leukemia (137), and colorectal cancer (138). During the deficiency (134). In addition, plasma thiamine levels are growth of Ehrlich’s ascites tumor, the concentration of TDP decreased by 76% in type 1 and 75% in type 2 DM; in the liver of tumor-bearing animals continuously drops for decreased plasma thiamine levels have also been associated 10 days after inoculation, and the TDP level in the tumor with increased renal clearance and fractional excretion of itself decreases more abruptly by the terminal period of thiamine (134). Furthermore, thiamine transporter protein tumor growth (10th day) (139). Some authors have suggested concentrations are increased in erythrocyte membranes in that thiamine supplementation may contribute to the high type 1 and type 2 DM. Therefore, changes in thiamine levels rate of tumor cell survival, proliferation and chemotherapy may be masked by an increase in thiamine transporter resistance (140). A significantly higher incidence of urinary expression (134). bladder carcinomas was induced in rats fed bracken fern,

173 CANCER GENOMICS & PROTEOMICS 10 : 169-186 (2013) which contains a carcinogen agent, and additionally exhibited enhanced DNA damage in end-stage renal disease, supplemented with thiamine than observed in rats fed only independent of changes in the plasma levels of advanced bracken fern (141). In melanoma cells, overexpression of the glycation end product (154). melanoma tumor antigen p97 resulted in decreased thiamine triphosphatase levels that may lead to greater TPP and Matrix metalloproteinases (MMPs). MMPs are proteolytic increased cellular proliferation (142). TPP inhibits enzymes responsible for both extracellular matrix (ECM) cytotoxicity of methotrexate, an antimetabolite used for the remodeling and the regulation of leukocyte migration through treatment of cancer (143). In vitro , thiamine blocks the the ECM, which is an important step in the inflammatory antitumor effect of mechlorethamine in murine leukemia processes. MMP overexpression has been reported in many cells (144) and blocks the antitumor effect of cyclophosphan types of cancer, including malignant peripheral nerve sheath in Ehrlich’s ascites tumor (145). The administration of tumors (155), non-small cell lung cancer (156), glioblastoma cyclophosphan further increased thiamine deficiency in multiforme (157), sarcoma (158), colorectal cancer (159), tumor-bearing mice. Simultaneous administration of prostate cancer (160), and ovarian carcinoma (161). MMP thiamine and cyclophosphan abolished the cytostatic toxic polymorphisms are associated with breast cancer (162), effect but did not affect their antitumoral properties (145). colorectal cancer (163), renal cell carcinoma (164), adult Furthermore, low thiamine levels were of benefit against astrocytoma (165), endometrial carcinoma (166), bladder some types of cancer s. Thiaminase I digests thiamine and cancer (167), epithelial ovarian cancer (168), oral cancer (169), has been reported to have a growth-inhibitory activity against cervical cancer (170), esophageal squamous cell carcinoma breast cancer cell lines (146) and lymphoid leukemia cell (171), gastric cancer (172), malignant head and neck tumors lines (147). In addition, MDA231 breast cancer xenografts (173), hypophyseal adenoma (174), prostate cancer (175), exhibited growth delay in mice fed a thiamine-free diet glioblastoma multiforme (176), and HCC (177). In meta- (146). Injections of oxythiamine increased the rate of analyses, MMP-2 polymorphisms have been linked to the risk pathological mitoses in Walker 256 carcinoma cells, reduced of lung ( -735 C/T ) (178) and breast cancer ( -1306 C/T ) (179), the tumor weight by 45%, and inhibited the synthesis of TDP but MMP-2 -1306 C/T allele may be a protective factor for and activity of transketolase in tissues (148). However, digestive cancer risk (180). In other studies, polymorphisms of marginal dietary thiamine deficiency induces the formation the MMP-1, -2, 3 , and - 7 may have played allele-specific roles of aberrant colonic crypt foci in rats (149). In Syrian in cancer development (181, 182). However, MMP-9 has also hamsters, which are susceptible to oral tumor induction by been shown to be up-regulated in the TD mouse brain (183, chemical agents, a dietary regime low in thiamine resulted 184). Thiamine reduces the MMP-2 activity in the heart of in the development of malignant neoplasm s arising in the diabetic rats and prevents diabetes-induced cardiac fibrosis pouch epithelium in a significantly shorter period of time (185). Moreover, thiamine and benfotiamine correct the than in hamsters fed a diet containing adequate amounts of increase in MMP-2 activity that results from high glucose this vitamin (150). Moreover, thiamine did not induce death levels in human retinal pericytes, while increasing tissue or increase the proliferation rate of Hepa or HepG2 HCC cell inhibitor of metalloproteinase-1 (TIMP-1) (186). Altogether, lines, either in vitro or in vivo , and thiamine was reported to these studies suggest that thiamine may play an important role attenuate Wilson’s disease-induced HCC (151). In another in the pathological processes of cancer by modulating the report, thiamine did not stimulate tumor growth in patients levels of MMPs and TIMPs. with gastric tumors (145). In a patient with osteosarcoma, subcutaneous perfusion of thiamine reduced the tumor Prostaglandins (PGs) and Cyclooxygenase-2 (COX2). PGS circumference from 30 to 20 cm, equivalent to a reduction play a role in inflammatory processes. COX participates in the of 50-75% in volume, within two days (152). A metabolic conversion of arachidonic acid into PGs. The expression of control analysis demonstrated a high stimulatory effect on COX2 mRNA and PGE 2 were selectively increased in tumor growth of 164% compared with controls with a vulnerable regions in the symptomatic stages of TD thiamine dose of 25-fold the recommended dietary allowance encephalopathy animal models (187). Up-regulation of 15- (RDA); however, at very high doses of thiamine, ~2500-fold hydroxyprostaglandin dehydrogenase (15-PGDH) expression the RDA, the opposite effect was observed, producing an was observed in breast cancer cell lines transfected with inhibitory effect on tumor growth of 36% compared with SLC19A3 gene and down-regulation was observed after control animals (153). The Authors suggested that when suppression of SLC19A3 with siRNA vectors (188). thiamine supplementation is necessary for patients with Overexpression of 15-PGDH inhibited interleukin (IL-1β)- cancer, it should be administered at high doses to avoid the induced COX2 expression (189). In murine macrophages, tumor-promoting effect of low doses. Furthermore, thiamine benfotiamine also blocked the expression of COX2 and its analog benfotiamine significantly reduced genomic damage product PGE 2 by lipopolysaccharide (LPS)-induced of peripheral lymphocytes in hemodialysis patients, who cytotoxicity (190). In addition, benfotiamine significantly

174 Lương et al : Thiamine and Cancer (Review) prevented LPS-induced macrophage death and monocyte analyses, manganese SOD polymorphisms may contribute to adhesion to endothelial cells. These anti-inflammatory effects cancer development ( Val-9Ala ) (234) and prostate cancer of benfotiamine are mediated through the regulation of the susceptibility ( Val-16Ala ) (232) but not breast cancer arachidonic acid pathway in macrophages (191). Tumor susceptibility ( Val-16Ala ) (233). However, oxidative stress has inflammation is now recognized as one of the hallmarks of been associated with region-specific neuronal death, and lipid cancer. Over-expression of COX2 has been associated with peroxidation products accumulated in the remaining thalamic resistance to apoptosis, increased angiogenesis and increased neurons after 11 days of TD animal models (234). In vitro , tumor invasiveness in various types of cancer. Increased COX2 thiamine inhibits lipid peroxidation in rat liver microsomes expression has been reported in endometrial adenocarcinoma and free radical oxidation of oleic acid (235). Benfotiamine (192), breast cancer (193), reno-medullary interstitial cell promotes a reduction in ROS-induced by advanced glycated tumor (194), colorectal carcinomas (195), gastric cancer (196), albumin in macrophages (236). In primary human peritoneal carcinoma of the cervix (197), and familial adenomatous mesothelial cells of a rat model of peritoneal dialysis, the polyposis (198). Deletion of Cox2 in mouse mammary addition of benfotiamine enhanced transketolase activity and epithelial cells delayed breast cancer onset (199). COX-2 reduced expression of advanced glycation end products and inhibitors also reduced the growth and induced regression of their receptor (237). These data suggest that benfotiamine human esophageal adenocarcinoma xenografts in nude mice protects the peritoneal membrane and remnant kidney in such (200), and retarded murine mammary tumor progression by a rat model. Thiamin rescues hepatocytes from iron-catalyzed reducing tumor cell migration, invasiveness, and angiogenesis oxidative stress by reducing lipid peroxidation, mitochondrial (201). Genetic variability in enzymes could impact on the risk and protein damage and DNA oxidation (238). These findings of the disease. COX2 polymorphisms have been associated suggest that thiamine modulates oxidative stress in cancer. with bladder (202), biliary tract (203), lung (204), non- melanoma skin cancer after organ transplantation (205), Nitric oxide synthase (NOS). NOS is an enzyme involved in esophageal squamous cell carcinoma (206), nasopharyngeal the synthesis of nitric oxide (NO), which regulates a variety carcinoma (207), pancreatic (208), invasive ovarian carcinoma of important physiological responses, including cell (209), breast (210), gastric carcinoma (211), acute myeloid migration, immune response and apoptosis. NO and calcium leukemia (212), prostate (213), head and neck (214), colorectal have been reported to regulate mitochondrial biogenesis in adenoma (215), and HCC (216). In meta-analyses, the COX2 follicular thyroid carcinoma cells (239). There is a link 1195G>A polymorphism was significantly associated with an between NO and the induction of apoptotic cell death in head increased risk of digestive system cancer, especially in Asian and neck squamous cell carcinoma development (240). populations (217), and the -765G>C variant may confer an Cytokines especially interferon-gamma was found to induce increased risk of colorectal carcinoma and esophageal cancer in apoptosis in acute leukemia via the NO and caspase-3 Asians. The 8473T>C polymorphism may confer a decreased pathway (241). The reduction of NO enhanced the risk of breast and lung cancer (218). In addition, PGE 2 has been radiosensitivity of hypoxic non-small cell lung cancer (242). reported to be associated with colorectal adenoma (219), Increased NO may be a sign of subclinical cardiotoxicity of pancreatic tumor (220), and childhood neuroblastoma (221). The doxorubicin (243). High NO concentrations at the periphery suppression of PGE 2 receptor inhibited human lung carcinoma of a melanoma may contribute to metastasis by stimulating cell growth (222). These findings suggest that thiamine may cell proliferation, inhibiting apoptosis, or acting as a play a role in modulating the inflammatory process of cancer. lymphangiogenic factor (244). Inducible NOS (iNOS ) mRNA expression was considerably higher in glioblastoma than Reactive oxygen species (ROS) . ROS play a major role in meningioma specimens (245). iNOS expression has been various cell-signaling pathways. ROS activates various correlated with angiogenesis, lymphangiogenesis, and poor transcription factors and increases in the expression of proteins prognosis in gastric cancer (246) and in estrogen receptor- that control cellular transformation, tumor cell survival, tumor negative breast cancer (247). NOS inhibition enhanced the cell proliferation and invasion, angiogenesis, and metastasis antitumor effect of radiation in the treatment of squamous (223). ROS also play an important role in the initiation and carcinoma xenografts (248). NOS polymorphisms have been progression of many types of cancer (224-229). Single- associated with bladder (249), urothelial carcinoma (250), nucleotide polymorphisms of antioxidant defense genes may gastric (251), colorectal cancer (252), and non-Hodgkin’ s significantly modify the functional activity of the encoded lymphoma (253). In a meta-analysis study, the endothelial proteins. Women with genetic variability in iron-related NOS 894G>T polymorphism was associated with breast oxidative stress pathways may be at increased risk for cancer (254). However, increased brain endothelial NOS postmenopausal breast cancer (230). The Ala variant of expression was demonstrated in TD (255). In murine superoxide dismutase (SOD) has been associated with a macrophages, benfotiamine was also found to block the moderately increased risk of prostate cancer (231). In meta- expression of iNOS by LPS-induced cytotoxicity (189).

175 CANCER GENOMICS & PROTEOMICS 10 : 169-186 (2013)

Figure 1. Summary the role of thiamine in cancer.

Table II. The role of thiamine in cancer.

Cancer Thiamine

Diabetes mellitus *Increased risk of cancer. *Low plasma thiamine levels. Cancer *Low plasma thiamine levels. Matrix metalloproteinases (MMP) *Overexpression of MMPs is observed in cancer *MMP polymorphisms have been associated with cancer. *Thiamine and benfotiamine reduce MMP levels. Prostaglandins (PGs) and *Overexpression of COX2 and PGE 2 has *Benfotiamine inhibits COX2 and Cyclooxygenase 2 (COX2) been reported in cancer. PGE 2 expression. *COX2 polymorphisms have been associated with cancer. Reactive oxygen species (ROS) *ROS have been suggested to play a role in cancer. *Thiamine reduces ROS. Nitric oxide synthase (NOS) *iNOS expression increases in cancer. *Benfotiamine inhibits iNOS expression. *NOS polymorphisms have been associated with cancer.

Table II illustrates the role of thiamine in cancer and non-genomic mechanisms, which include protein expression, Figure 1 summarizes the role of thiamine in cancer. oxidative stress, inflammation, and cellular metabolism. Thiamine supplementation may stimulate a high rate of tumor Conclusion cell survival, proliferation and chemotherapy resistance, but other studies have demonstrated the beneficial role of Genetic studies have provided opportunities to determine thiamine in cancer. However, thiamine deficiency may occur which proteins may link thiamine to cancer pathology, in patients with cancer and may produce serious disorders, including SLC19 gene, transketolase, transcription factor p53, including Wernicke’s encephalopathy, that require parenteral PARP, and NOX. Thiamine can also act through a number of thiamine supplement ation . In the early stages of TD

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Breast Cancer Res Treat 124 : 809-813, 2010. Savagner F: Nitric oxide and calcium participate in the fine 255 Kruse M, Navarro D, Desjardins P and Butterworth RF: Increased regulation of mitochondrial biogenesis in follicular thyroid brain endothelial nitric oxide synthase expression in thiamine carcinoma cells 286 : 18229-18239, 2011. deficiency: relationship to selective vulnerability. Neurochem Int 240 Bentz BG, Chandra R, Haines GK 3rd, Robinson AM, Shah P 45 : 49-56, 2004. and Radosevich JA: Nitric oxide and apoptosis during human 256 Luong K and Nguyen L: The impact of thiamine treatment on head and neck squamous cell carcinoma development. Am J generalized anxiety disorder. Int J Clin Med 2: 439-443, 2011. Otolaryngol 23 : 4-11, 2002. 241 Siripin D, Fucharoen S and Tanyong DI: Nitric oxide and Received April 12, 2013 caspase 3 mediated cytokine induced apoptosis in acute Revised May 3 2013 leukemia. Asian Pac J Allergy Immunol 29 : 102-111, 2011. Accepted May 9, 2013

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